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1
Desjardine, Kelsey Lorne. "Bioactive marine natural products". Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/31286.
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The chemical exploration of extracts from cultures of the marine bacterial isolate PNG-276 yielded the novel antibiotic tauramamide (2.13), a non-ribosomal peptide active against cultures of Enterococcus sp. and methicillin-resistant Staphylococcus aureus (MRSA). A study of extracts of the marine sponge Spirastrella coccinea yielded the novel macrolide methylspirastrellolide C (3.14), which is active against protein phosphatase 2A (PP2A). A third study examined sponge extracts active in a cannabinoid receptor assay, yielding two known compounds, an A- nor -steroid derivative (4.10) and bengamide A (4.11). Neither purified compound was active in the cannabinoid receptor assay, although in both cases this is the first report of these compounds being isolated from Stylissa massa and Hemiasterella aff. affinis sponges, respectively. [See Thesis for Diagrams]Science, Faculty of
Chemistry, Department of
Graduate
2
Al-Zereini, Wael. "Natural products from marine bacteria". [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=982197985.
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Reddy, Priyanka, e saipriyanka@gmail com. "Studies in Marine Natural Products". RMIT University. Applied Sciencez, 2009. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20091023.091658.
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The focus of this thesis was to study the chemotaxonomic relationship of selected southern Australian marine brown algae of the genera Cystophora and Sargassum. Consequently, this resulted in the isolation and structure elucidation of six new terpenoids from two southern Australian marine brown algae Cystophora moniliformis and Sargassum fallax together with 10 previously reported natural products. As a result of the re-isolation of these known secondary metabolites, updated and complete structural characterisation data could be provided for the first time for 7 of these compounds. Chemotaxonomic studies of Cystophora moniliformis resulted in the isolation of two new cyclic epimeric terpene diols moniliforminol A (3.25) and moniliforminol B (3.26), a new linear farnesyl acetone derivative (3.27) and the previously described terpenoids (3.19)-(3.24). This study also resulted in the first complete 2D NMR characterisation for compounds (3.21) to (3.24) as well as the first report of (3.24) occurring as a natural product. All structures were elucidated by detailed spectroscopic analysis with the relative configurations of (3.25) and (3.26) being established by selective 1D nOe NMR experiments. The proposed biosynthetic pathway for the above compounds has also been described. Chemical investigation of the Southern Australian marine brown alga Sargassum fallax resulted in the isolation of three new meroditerpenoids fallahydroquinone (4.8), fallaquinone (4.9) and fallachromenoic acid (4.10), together with the previously reported compounds sargaquinone (4.1) (isolated and identified in a mixture with sargaquinoic acid), sargahydroquinoic acid (4.2), sargaquinoic acid (4.3) and sargachromenol (4.11). As a result of this study the complete 2D NMR characterisation for sargahydroquinoic acid (4.2) and sargaquinoic acid (4.3) could also be reported for the first time. All structures were elucidated by detailed spectroscopic analysis. Sargahydroquinoic acid (4.2) and sargaquinoic acid (4.3) displayed moderate antitumour activity.
4
Kirkham, James E. D. "Synthesis of marine natural products". Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442593.
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Prinsep, Michéle. "Studies in marine natural products". Thesis, University of Canterbury. Chemistry, 1990. http://hdl.handle.net/10092/7256.
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Two new β-carboline alkaloids were isolated from the bryozoan Cribricellina
cribraria. One of these, 1-vinyl-8-hydroxy-β-carboline, was the major cytotoxic component of the extract, while the other had a novel sulphone structure. Several other known β-carboline alkaloids were also isolated from the extract. To investigate structure-activity relationships in these compounds, several derivatives of the major alkaloid were prepared and a number of 1-substituted β-carboline alkaloids synthesised. Nmr spectroscopic studies of these compounds were carried out and previously published ¹³C nmr data for some of these compounds revised. Homarine was isolated as the major water soluble component of the extract and the sterol composition examined. Known β-carboline alkaloids were isolated from the related
bryozoan Margaretta barbata.
The known biologically active compounds, girolline and hymenialdisine were isolated from the sponge Axinella sp. 2. As some discrepancies between the experimental and published data on hymenialdisine were noted, an X-ray crystal structure analysis was performed. Oroidin, homarine and taurine were also isolated from the extract and the sterol composition found to consist exclusively of ring-contracted A norstanols.
An extract of the sponge Stylopus australis was found to contain a new sterol sulphate and two derivatives of this compound were prepared. The full assignment of the ¹H nmr spectrum of the sulphate was achieved with the aid of COSY, nOe, HETCOR and XCORFE nmr experiments. The glyceryl ether, chimyl alcohol was also isolated from the sponge.
An extract of the related sponge, Hymedesmia sp. 1 was examined and rhodoic acid isolated as the major water soluble component, along with homarine. The sterol compositions of Stylopus australis and Hymedesmia species 1 and 2 were examined for comparative purposes.
Studies on an extract of the sponge Hymeniacidon hauraki led to the isolation of a new furan fatty acid. The sterol corbisterol and its peroxide were isolated from one sample of the sponge and this led to an examination of infraspecific sterol variation in this species.
A screening procedure of biologically active natural product extracts has been developed. The procedure involves examining the chromatographic behaviour of the biological activity of an extract and is designed to detect known biologically active compounds and to determine the best means of handling extracts containing unknown biologically active components.
6
Stirling, David J. "Studies on marine natural products". Thesis, University of Canterbury. Chemistry, 1996. http://hdl.handle.net/10092/7815.
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An investigation of the marine sponge Halisarca sp. was carried out following the discovery of strong activities in antiviral and P388 murine leukaemia assays of an extract from this sponge. A polyether type of compound is suspected as the cause of this activity. The investigation of Halisarca sp. made a significant contribution to the development of a chemical screening process.
The absolute configuration of pateamine has been elucidated by a combination of degradative and synthetic chemistry utilising formation of diastereoisomers with Mosher's acid. Several other derivatives of pateamine are reported.
The algal metabolite thyrsiferol has been isolated from the digestive gland of the marine mollusc Aplysia parvula. The egg masses of A. parvula have also been examined.
The NMR characterisation of the thyrsiferol has been extended through the extensive use of one- and two- dimensional spectroscopic experiments.
7
Hart, Joanne B. "Studies on marine natural products". Thesis, University of Canterbury. Chemistry, 1995. http://hdl.handle.net/10092/7850.
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The halichondrins are a series of polyether macrolides displaying potent in vitro and in vivo antitumour activities and, as such, represent important leads as anticancer drugs. These compounds had previously been isolated from a number of unrelated marine sponges, such as Lissodendoryx sp., a high yielding deep-water sponge located off the Kaikoura coast of New Zealand.
Structure-activity relationships in the halichondrin senes have now been investigated. Hemi-synthetic modifications of selected naturally-occurring halichondrins have produced over fourteen new analogues. The biological activities of twelve of these analogues have been assessed in an in-house P388 in vitro assay and in the National Cancer Institute's (USA) in vitro sixty cell-line human tumour panel. An analysis of these data has shown that the lactone ring (C1-C30), the olefinic functionalities (C19 and C26), the natural C38 stereochemistry and the tricyclo ring system (C-E rings) are essential structural features of the halichondrins.
The characterisation of the hemi-synthetic derivatives has been facilitated by the full NMR spectroscopic assignments of halichondrin B and homohalichondrin B.
The future progress of the halichondrins as anticancer drugs will have been assisted by the development of an understanding of the general chemistry of the halichondrins.
8
Barrow, Colin James. "Studies in marine natural products". Thesis, University of Canterbury. Chemistry, 1988. http://hdl.handle.net/10092/8598.
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The bioactivity directed analysis of the extract from a sponge of the genus Sarcotragus led to the isolation of a series of bioactive sesterterpenes, of which variabilin (1a) was the major component. The sesterterpenes (29a), (30) and (31a), along with the related C₂₁ furanoterpene (32), were present in lesser amounts. The unequivocal assignment of the stereochemistry of the 20,21 double bond in variabilin as 20(Z) was achieved through examination of the22-O-methyl derivative (1b) of variabilin and the isolation of the variabilin isomer (29a) with the 20(E) stereochemistry.
Variabilin was also isolated from a sponge of the genus lrcinia. The four related bioactive sesterterpenes (33b), (34b), (35b), and (36b) together with (31b) were isolated from a methylated extract from the same sponge.
Variabilin autooxidised in the presence of light and air to form a mixture of products that underwent further oxidation on standing. The 22-O-methyl derivative (1b) of variabilin did not autooxidize but underwent oxidation in the presence of the singlet oxygen sensitizer, rose bengal. The products from this oxidation reaction were (48b), (49b), (50b), (51b), (52b), (53b), (50b), (61b), (62b), (63b), (64b) and (65b) and these were the same as the products from the variabilin autooxidation with the exception of the methyl group at C₂₂. Variabilin autooxidation was shown to occur through the production of singlet oxygen and subsequent oxygen addition to the furan moiety. The production of singlet oxygen occurred through a sensitization mechanism involving the variabilin tetronic acid moiety.
To investigate structure-bioactivity relationships in variabilin and related sesterterpenes, derivatization of the furan and tetronic acid moieties in variabilin was carried out. 22-O-Me variabilin (1b), in contrast to variabilin, reacted favourably under most furan reaction conditions and so a number of reactions were carried out on (1b) also. Hydrogenation of variabilin gave the cytotoxic compound (73). Dials-Alder addition of DMAD to variabilin gave the cytotoxic compounds (74a) and (75a) and acylation gave the cytotoxic compounds (81) and (82). Reduction of these acylation products gave the cytotoxic derivatives (83) and (84). The non-cytotoxic compound (85) was formed on reaction of p-bromobenzoylchloride with variabilin. Dials-Alder addition of DMAD to 22-O-Me variabilin gave the cytotoxic compounds (74b) and (75b) and addition of 4-phenyl-1,2,4-triazoline-3,5-dione (phenyl-TD) (78) gave the potential antiviral compounds (76) and (77).
A cytotoxic sesquiterpene (86) with a tricyclo[6.3.1.0.²,⁵]dodecane skeleton has been isolated from the extract of a New Zealand Eurypon sp. of sponge. Two derivatives, (87) and (88), of this sesquiterpene have also been isolated, probably as artefacts arising during the isolation procedure. The structure of a spirosesquiterpene (89), also obtained from the sponge extract, has been determined. Previously published nmr assignments for β-caryophyllene alcohol (90) have been revised. Three further compounds, labeled unknowns a-c, were isolated, but their structures were not determined. One of these unknowns (unknown a) was probably a sesquiterpene, and was shown to be cytotoxic, while the remaining two (unknowns band c) gave spectroscopic data which indicated that while they were very closely related to one another, they were not sesquiterpenes.
Bioassay directed isolations of the active components from a new sponge, genus Chondropsis, and the bryozoan, Margaretta barbata, were attempted. The bryozoan, Margaretta barbata had previously been shown to exhibit significant in vivo P388 activity. For the Chondropsis species the components responsible for the observed biological activity appeared to be very minor components of the overall sponge and isolation of the active compounds was not achieved. For the bryozoan the more polar active material was present in reasonable abundance and a compound (unknown d) giving in vitro P388 activity was isolated. However full characterisation of this compound was not achieved. The compound, or compounds, responsible for the biological activity shown by the less polar material were not isolated.
Sterols were shown to be major components of the non-polar organic material in both the sponge and bryozoan species studied. For the Chondropsis sponge the major sterol component was identified as 24-methylene-cholesterol (92). For the bryozoan, Margaretta barbata, the major sterol was identified as cholesterol (93) with 24-methylene-cholesterol (92) and cholest-4-en-3-one (94) also being identified. The major organic water soluble compound was identified as homarine (95).
9
Bringans, Scott D. "Studies on natural product derivatives : HIV therapies incorporating marine natural products". Thesis, University of Canterbury. Chemistry, 2001. http://hdl.handle.net/10092/6699.
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CV-N is an 11 kDa, anti-HIV protein that binds strongly to the envelope glycoprotein, gp120, expressed on the outer surface of the free virion and also on HIV-infected cells. As such, it represents an important lead for development of anti-HIV therapeutics. Marine toxins such as the halichondrins have potent in vivo cytotoxicities and are lethal to cells. The combination of this potency of the marine toxins with the unique targeting capability of CV-N has been harnessed to produce conjugates that have the potential to selectively target and eliminate HIV-infected cells.
Three forms of the protein were developed; the native protein itself, a derivative recombinantly produced in E. coli with an extra cysteine at the C-terminal (CV-N-Cys) and CV-N with the lysine side chain amines converted into thiols (thiolated-CV-N).
To facilitate release of the toxin within infected cells an enzymatically-cleavable pHdependent biolinker was incorporated separating the toxin from the protein. The chemistry required for incorporation of protein, biolinker, and toxin, was established through synthesis of fluorescently labelled conjugates capable of reaction with CV-N. Biological testing of these derivatives showed no interference with the anti-HIV activity of the CV-N when conjugated in these model compounds. Synthetic strategies were developed to produce two derivatives of norhomohalichondrin B amine, both containing the cleavable biolinker, but with activation from succinimidyl esters and maleimido groups respectively.
Native CV-N was reacted with the succinimidyl ester derived toxin construct to produce a CV-N-biolinker-toxin conjugate. The maleimido derivative toxin construct was reacted with both CV-N-Cys and thiolated-CV -N to produce closely related CV-N-toxin conjugates. Investigations into the binding properties and cell toxicities of these conjugates is currently underway.
10
Thornhill, Andrew John. "Synthetic studies towards marine natural products". Thesis, Bangor University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364987.
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Rowley, David Chapman. "Antiviral natural products from marine sources /". Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2001. http://wwwlib.umi.com/cr/ucsd/fullcit?p3035894.
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Lorente, Crivillé Adriana. "Marine Natural Products. Synthesis and structure determination". Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/279367.
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Natural products from terrestrial plants and microorganisms have long been a traditional source of drugs. For centuries humans have been looking on their environment for medicines to treat illnesses. But unlike terrestrial sources, marine habitat has not been so extensively studied; this field awaited refinements in technologies to collect the source organisms, and development of more advanced analytic techniques to better understand the more complex isolated compounds. Since 1950s this field has suffered an exponential push; considering that water covers around a 70% of the earth’s surface, and 32 of the 33 animal phyla are represented in aquatic media, marine habitat represents an extensive source of new bioactive molecules.
Synthesis represents a powerful tool to use on our behalf for structure determination and supply of material for clinical tests on the development of new bioactive drugs. This thesis is focused on the synthesis and structure determination of bioactive compounds isolated from marine habitat: barmumycin and phormidolides B-D. Our strategy lied on the identification of the target by comparison of the available data from the natural product with data of our synthetic compounds.
Barmumycin was isolated from an extract of a marine actinomycete and found to be cytotoxic against various human tumor cell lines. Macrolactone 1 was assigned on the basis of 1H and 13C NMR spectroscopy. Compound 1 was synthesized by two different routes. The main goal of both our synthesis is the alkylation of a weak nucleophilic aniline by this two different methods, which are based on a reductive amination and on a nucleophilic substitution.
However, major spectroscopic differences between isolated barmumycin and 1 led to revision of the proposed structure. New structure 2, based on a pyrrolidine with an exocyclic double bond linked to an aromatic ring by an amide bond, was proposed. On the basis of the enantioselective synthesis of this new compound, and subsequent spectroscopic comparison of it to an authentic sample of barmumycin, the structure of the natural compound was indeed confirmed as that of 2.
Polyketide macrolides are a class of secondary metabolites with interesting biological activities and complex structure and stereochemistry. A general overview of THF-containing macrolactones has been compiled, a class of compounds with high potential as drug candidates. Described are isolation, structure determination and the described synthesis up to 2012.
Phormidolides B-D are polyketide macrolides related to oscillariolide and phormidolide A. These compounds were isolated from an active organic extract of a sponge of the Petrosiidae family and presented antitumor activity. The planar structure of Phormidolides B-D was determined on the basis of comparison of the spectra of the natural product with oscillariolide and phormidolide A and with the study of NMR spectra of isolated compounds. The relative stereochemistry of the macrocyclic core was only determined for 4 out of the 6 stereocenters of the macrocycle. The next target of this thesis is the enantioselective synthesis of the macrocyclic core of phormidolides B-D.
The best synthetic pathway to the synthesis of the macrolide core of phormidolides B-D was selected with a not-stereoselective synthetic study. A strategy based on an olefin metathesis was discarded. On the other hand a strategy based on a Julia-Kocienski olefination completed the preparation of the macrocycle as a mixture of diasteromers.
A robust and efficient methodology for the enantioselective synthesis of the macrolide core of phormidolides B-D was developed from the Julia-Kocienski olefination route. The strategy is versatile and can be used for the synthesis of the different diastereomers of the macrocycle making the appropriate changes in the starting materials and chiral inductors. The selective synthesis of the Z-trisubstituted double bond present on the macrocyclic core of phormidolides B-D was the objective of an optimization process that culminated with the use of a 1-(tert-butyl)tetrazolyl sulfone to succesfully afford the formation of the endocyclic alkene with excellent stereoselectivity.
It is a fact that the discovery of New Molecular Entities (NME) requires innovation, new ideas and processes. Scientists have learned over the years how to overcome the problems often associated with marine derived natural products development and this work is one more example of this scenario.Els productes naturals extrets de plantes i organismes terrestres han estat durant molts anys font d’inspiració per a la preparació de fàrmacs. Per contra el medi marí no ha rebut tanta atenció, la química dels productes naturals marins ha hagut d’esperar que les tecnologies es modernitzessin per facilitar la recol•lecció de mostres i la determinació estructural dels productes extrets, que presenten molta més complexitat estructural que els productes d’origen terrestre. En els últims 50 anys, aquest camp ha estat objecte de gran interès ja que representa una font de noves molècules bioactives, amb estructures i mecanismes d’acció diferents dels coneguts. En aquesta tesi s’ha treballat en dos projectes focalitzats en l’estudi de molècules d’origen marí com a fàrmacs, utilitzant la síntesi com a eina en els primers estadis de desenvolupament ja que la quantitat aïllada de les fonts naturals només serveix per fer una primera aproximació a estructura i activitat. La barmumicina és un producte natural amb activitat biològica del que s’ha confirmat l’estructura gràcies a la síntesi. El compost que es va determinar en la primera assignació s’ha obtingut per síntesi i s’ha comparat amb el producte natural duent a la conclusió que l’estructura no era la correcta. La reassignació i síntesi d’una nova molècula proposada ha confirmat la identitat d’aquest producte natural. Les formidolides B-D són productes naturals d’alta complexitat estructural. S’ha desenvolupat la síntesi del fragment macrocíclic de les formidolides B-D, abordant dues aproximacions per a la formació de l’alquè trisubstituit; una basada en una metàtesi d’olefines i l’altra en una olefinació de Julia-Kocienski. La segona ruta s’ha seleccionat com a ruta per adaptar a procediments estereoselectius. Adaptant aquesta estratègia, s’ha desenvolupat una metodologia que permet sintetitzar eficaçment i de forma enantioselectiva el macrocicle de les formidolides B-D; l’estratègia és versàtil, ja que canviant els materials de partida o els auxiliars quirals es pot dirigir la síntesi cap al diastereòmer desitjat. El punt clau de la síntesi ha estat la formació del doble enllaç trisubstituitZ amb bon rendiment i selectivitat, pel qual s’ha dut a terme una optimització del procés. S’han sintetitzat tres estereoisòmers i la comparació dels espectres de RMN del producte natural i els sintètics ha permès establir la configuració relativa dels esterocentres que presenta la macrolactona del producte natural. Els resultats presentats demostren la utilitat de la síntesi en el desenvolupament de productes naturals, ja sigui en la determinació d’estructura, estereoquímica o en la producció en sí.
13
Loosley, Benjamin Charles. "Efforts towards syntheses of marine natural products". Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/63303.
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This thesis describes work attempting to synthesize and derivatize marine natural products. Chapter 1 outlines a brief history of natural products chemistry. It explains why modern medicines are commonly derived from natural sources using historical examples. It also explains why natural products chemists have turned to organisms in the oceans for exploration into new and unique molecular frameworks and biological activities.
Chapter 2 describes the work done towards total synthesis of the marine natural product cladoniamide G. The successful approach involves coupling a halogenated 2,2-bisindole with an unsymmetric, tricarbonyl electrophile. It also describes work towards synthesis of analogues, including attempts to glycosylate the natural product.
Chapter 3 is the first chapter that discusses work towards total synthesis of a second marine natural product, nahuoic acid A. This chapter focuses on synthesis of a linear cycloaddition precursor that resembles an intermediate in the presumed biosynthetic pathway. The work in this chapter culminates in attempts at a Diels-Alder reaction to form a cis-decalin system.
Chapter 4 also focuses on work towards total synthesis of nahuoic acid A. However, the work in this chapter uses a Diels-Alder reaction to form a cis-decalin system early, and then focuses on the challenges of functionalizing the decalin. Four general approaches to functionalization are investigated: conjugate additions, nucleophilic substitutions, sigmatropic rearrangements, and metal catalyzed cycloisomerizations.Science, Faculty of
Chemistry, Department of
Graduate
14
Phipps, Richard K. "Natural products from marine derived micro-organisms". Thesis, University of Canterbury. Chemistry, 2002. http://hdl.handle.net/10092/5796.
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A large number of micro-organisms were cultured from marine substrates collected from multiple sites along the coast of the South Island of New Zealand. Depending on growth rate and colony morphology the micro-organisms were classified as terrestrial, facultative marine or obligate marine. Micro-organisms were selected for large scale culture and extraction based on either apparent unusual morphology or observed cytotoxicity in small scale extracts.
Two very pale yellow compounds were isolated from cytotoxic extracts prepared from culture broths of a Fusarium sp. The first compound (A) was identified as a novel trichothecene called 4-deacetoxy-8-isobutyrylneosolaniol. The second compound (B) was identified as the 4-hydroxy derivative of A, previously only known through semisynthetic preparation.
The known compound cephalochromin (C) was purified from the culture broths of two unidentified Cephalosporium-like Hyphomycetes. The identity with cephalochromin was confirmed by comparison of published NMR and circular dichroism spectroscopy. An intense yellow compound was isolated from an extract prepared from culture broths of an Alternaria sp. This compound was identified by NMR spectroscopy as a novel altersolanol called altersolanol J (D).
The known compound 1-hydroxyaclacinomycin T (E) was isolated from the culture broths of a Streptomyces sp. A further five related compounds (F - J) were also isolated the culture broths. Compounds F and G, were shown by NMR spectroscopy to be stereo isomers of pyrromycin called 9-epi-pyrromycin and (7R*9R*1OR*)-pyrromycin respectively. The low isolated mass of compound H prevented a complete identification but was tentatively assigned by NMR spectroscopy as an N-demethyl derivative of pyrromycin. Compounds I and J were both shown by NMR spectroscopy to be novel pyrromycin derivatives called 1-hydroxyauramycin T and 1-hydroxysulfurmycin T respectively.
The known compounds actinomycin V (K), actinomycin Xo (L) and actinomycin D (M) were purified from extracts of the culture broths of three Streptomyces sp.
The identities of all these compounds were established by 1D and 2D NMR spectroscopy and comparison to previously reported data.
15
Lill, Rachel E. "Studies on New Zealand marine natural products". Thesis, University of Canterbury. Chemistry, 1999. http://hdl.handle.net/10092/6078.
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The halichondrins, isolated from the Kaikoura sponge Lissodendoryx sp., are a series of polyether macrolides displaying potent in vivo antitumour activity. As such, they represent important leads as potential anticancer drugs. This research was focused on methodology that would enhance and complement the progress of halichondrins toward clinical trials.
A method was established for transforming 53-methoxyneoisohomohalichondrin B, an artefact of the methanol extraction method, to the more useful isohomohalichondrin B. A by-product of this acid treatment was identified as the C38 epimer of isohomohalichondrin B. The equilibrium character of the C38 epimerisation was studied.
The production of halichondrins by aquacultured Lissodendoryx sp. has been confirmed.
Haptens presenting the macrocyclic portion of the halichondrins were produced using three different linkers PMPI, PMSI and EMCR. The chemistry required to selectively oxidise the C26 methylene was established.
A polymer drug conjugate incorporating a halichondrin species has been prepared. This required the modification of homohalichondrin B to form an amino halichondrin.
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Mokhlesi, Amin [Verfasser]. "Natural Products from Marine Sponges / Amin Mokhlesi". Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2018. http://d-nb.info/1154306984/34.
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Ellithey, M. S. (Mona). "Bioactivity of marine organism-derived natural products". Thesis, University of Pretoria, 2013. http://hdl.handle.net/2263/43332.
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Background: HIV/AIDS is one of the most devastating diseases in the world with
approximately 36 million people living with the virus in 2012 and approximately 2.7
million new infections in that same year. Antiretroviral therapy (ART) successfully reduce
infection and decrease symptoms; but, the emergence of viral drug resistance due to
drug induced mutations in viral genes can render treatment ineffective. Infection with HIV
not only weakens the immune system leading to AIDS and increasing the risk of
opportunistic infections, but also increases the risk of several types of cancer. These
facts underscore an urgent need to develop new anti-HIV and cancer drugs with fewer or
no side-effects. Research into drug discovery and development using natural products is
increasingly becoming better established. Marine organisms as a source of natural
products delivered numerous novel compounds with sensational multiple
pharmacological properties. Thousands of novel compounds and their metabolites with
diverse biological activities ranging from antiviral to anticancer have been isolated from
various marine sources. With natural products, there are endless opportunities for
discovering novel compounds that can be used as drugs or backbones of drug leads. Methods: In this thesis, thirteen marine organisms were investigated for inhibitory
properties against HIV-1 enzymes as well as for potential cytotoxicity.
Cytotoxicity (The ability to kill cancer cells) of the extracts was determined using
tetrazolium dyes. Direct enzyme assays were used to determine the inhibitory properties
of the extracts against HIV-1 protease (PR) and reverse transcriptase (RT).
The most active extract Litophyton arboreum was then subjected to silica gel
chromatography in order to isolate, purify and identify the active compounds. These
active compounds were then tested for cytotoxic and HIV-1 enzyme inhibitory activities.
The cytotoxicity results were subsequently confirmed by real-time cell electronic sensing
and the enzyme studies were supported by in silico analysis docking using MOE
software. The most active compound (7β-acetoxy-24-methylcholesta-5-24(28)-diene-3,
19-diol) also underwent an ecological study that demonstrated the role of this compound
in the activity of the extract as well as the organism‘s seasonal distribution in its habitat.
The HPLC qualitative profiles of the seasonal total extracts were performed and the
concentration of the active compound in each extract was determined and related to the
activities and seasonal distribution of the organism in the community.
Results and discussion: Cytotoxicity results of the 13 marine organism‘s extracts in
(Hela, U937 and Vero cells) showed strong activity of L. arboreum against U-937 (IC50;
6.5μg/ml ±2.3) with a selectivity index (SI) of 6.45, while Sarcophyton trochliophorum
showed strong activity against HeLa cells (IC50; 5.2 μg/ml ±1.2) with an SI of 2.09. Other
species showed moderate to weak cytotoxicity against both cell lines. Two extracts
showed potent inhibitory activity against HIV-1 protease; these were Cassiopeia
andromeda (IC50; 0.84 μg/ml ±0.1) and Galaxura filamentosa (2.6 μg/ml ±1.3). It was
interesting to note that the most active extracts against HIV-1 PR, C. andromeda and G.
filamentosa showed no cytotoxicity in the three cell lines at the highest concentration
tested (100 μg/ml).
L. arboreum extract was the only extract that showed activities in all the bioassays
tested in this study. The bioassay-guided fractionation using different chromatographic
and spectroscopic techniques in the analysis of the Red Sea soft coral L. arboreum led to the isolation of nine compounds; Further fractionation and purification of the active
fractions resulted in the isolation and identification of nine known compounds (for which
the structures are provided in Figure 4.2) sarcophytol M (1), alismol (2), 10-O-methyl
alismoxide (4), alismoxide (5), (S)-chimyl alcohol (6), 7β-acetoxy-24-methylcholesta-5-
24(28)-diene-3,19-diol (7), erythro-N-dodecanoyl-docosasphinga-(4E,8E)-dienine (8), and
24-methylcholesta-5,24(28)-diene-3β,7β,19-triol (9).
Compound 7 demonstrated strong cytotoxicity against HeLa cells (CC50 4.3±0.8 μM),
with a selectivity index of SI 8.1 which was confirmed by real time cell electronic sensing
(RT-CES). Compounds 2, 7 and 8 showed strong inhibitory activity against HIV-1 PR at
IC50‘s of 7.2 ±0.7, 4.85±0.2 and 4.80 ±0.9 μM respectively. Docking studies gave
comparable scores when comparing the binding mode of the active compounds to that
of acetyl pepstatin, a known HIV-1 PR inhibitor. Interestingly, compound 8 showed potent
HIV-1 PR inhibitory activity and did not demonstrate cytotoxicity against the cell lines
used in the investigation. Also, compounds 2 and 5 showed cytostatic action in HeLa
cells where the compounds inhibited the cells proliferation but did not kill the cancer
cells; both compounds can be considered as potential leads in the development of
virostatic cocktails that medicine - A drug which inhibits viral replication.
Changes in the biological activities of the seasonal extracts of the soft coral L. arboreum
showed the highest activity in the autumn extract. The study also evaluated the
concentration of the active triterpene erythro-N-dodecanoyl-docosasphinga-(4E,8E)-
dienine) and its influence on the organism‘s maturation and distribution which showed a
positive correlation between the compound‘s concentration and oocyte maturation as
well as the dominance and distribution of the organism.
Conclusion: The findings presented in this thesis demonstrated that marine organisms
remain one of the most interesting sources for the discovery of bioactive compounds
against cancer and HIV. This study is the first to report the anticancer (cytotoxic behavior
specific for cancer cell lines) and anti HIV activities of most of the screened organisms. It
is also the first report for the metabolites isolation, identification and biological evaluation
of L. arboreum collected from Sharm El sheikh, Red Sea. Some of the isolated metabolites demonstrated potent anti-HIV-1 protease activity, with high safety margins.
The detailed IC50 study showed potent inhibitory activity of HIV-1 PR by compound 7β-
acetoxy-24-methylcholesta-5-24(28)-diene-3,19-diol [7] (IC50 4.8 μM), in addition to
compound 8 (4.86 μM), which also showed no toxicity against any of the cell lines under
investigation. This work and many other published reports support the high cytotoxicity of
polyhydroxylated sterols from marine organisms, which highlights the importance of this
chemical skeleton in the discovery of potential lead compounds from marine sources.
This study demonstrated a seasonal change in the biological activities of the soft coral L.
arboreum demonstrated the effect of the triterpene on the organism‘s maturation and
distribution. The autumn season appear to be the best time for L. arboreum collection for
biological purposes, where the highest distribution and highest intensity of the
compounds were found.
The findings presented here suggest that the screened Red Sea marine organisms
investigated could be an interesting source of bioactive compounds and deserve further
bioassay-guided isolation procedures to determine the identity and structure of the active
compounds. The biological activities of nine compounds isolated from L. arboreum
delivered promising leads for further biological evaluation.Thesis (PhD)--University of Pretoria, 2013.
lk2014
Biochemistry
PhD
Unrestricted
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Brastianos, Harry Charilaos. "Bioactive natural products from nature". Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/3960.
Texto completo da fonteResumo:
Bioassay guided fractionation of a crude extract of the marine sponge
Neopetrosia exigua resulted in the first reported isolation of exiguamines A
and B. These pyrroloquinone alkaloids have an unprecedented hexacyclic
skeleton that has not been previously encountered in natural products. Biological
studies have identified exiguamine A as a potent in vitro inhibitor of the
enzyme indoleamine-2,3-dioxygenase (IDO). IDO is an enzyme expressed by
tumor cells to evade the immune system. Inhibitors against this enzyme may
allow the immune system to attack cancer cells, making this enzyme a potential
drug target for anti-cancer agents.
Investigation of the crude extract of a Bacillus sp. collected in Dominica
led to the isolation of the known diketopiperazine cyclo(S-Val-S-Phe) (3.9). In
vitro biological studies revealed that cyclo(S-Val-S-Phe) is able to promote
neurite outgrowth, even in the presence of physiological inhibitors. In vivo
studies have shown that cyclo(S-VaI-S-Phe) is able promote sprouting in
serotonergic and adrenergic axons. Synthesis of the other three diastereomers
led to the discovery that cyclo(R-Val-R-Phe) is also an in vitro activator of
axonal outgrowth.
Inhibitors of the G2 checkpoint are able to increase the cytotoxicity of DNA
damaging chemotherapeutics. Bioassay guided fractionation of an extract of the
South American plant Duguetia odorata led to the isolation of the G2 checkpoint
abrogator, oliveroline. This investigation also led to the isolation of the
previously unreported alkaloid N-methylguatterine, and the known
alkaloids dehydrodiscretine and pseudopalmatine.
Chemical investigation of the marine sponge Myrmekioderma granulatum
led to the isolation of the new compounds abolenone and myrmekioside C, as well as the known compounds curcudiol, curcuphenol,
abolene and sesquiterpenoid. Biological studies of these
compounds revealed that curcudiol is a ligand of the sex hormone-binding
globulin. This protein is involved in transporting and regulating the
concentration of steroids such as testosterone and estradiol. Many pathological
conditions have a lower plasma concentration of these steroids. Ligands to
SHBG can release steroids into the blood, so this protein is a potential drug
target to treat conditions where a hormone insufficiency is present.
19
Gautschi, Jeffrey T. "Marine natural products from sponges and deep water, marine-derived fungi /". Diss., Digital Dissertations Database. Restricted to UC campuses, 2006. http://uclibs.org/PID/11984.
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Hickford, Sarah Jane Herbison. "Studies in the Chemistry of Marine Natural Products". Thesis, University of Canterbury. Chemistry, 2007. http://hdl.handle.net/10092/1429.
Texto completo da fonteResumo:
Compounds from the marine environment exhibit a wide variety of biological activities, and thus hold much promise as potential drugs. The halichondrins, isolated from the Kaikoura sponge Lissodendoryx sp. are no exception to this, demonstrating potent anticancer activity. Novel cytotoxic compounds have also been isolated from the Chatham Rise sponge Lamellomorpha strongylata. Knowledge of the cellular origins of such compounds is desirable, in order to establish if the sponge or associated micro-organisms are producing the compounds of interest. Siderophores are also important molecules, which are produced on demand by bacteria in order to obtain sufficient iron necessary for their growth. Knowledge of the biosynthesis of these compounds has potential for the control of undesirable bacteria, such as the anthrax-causing pathogen Bacillus anthracis. Cell separation studies have been carried out on Lamellomorpha strongylata, locating a swinholide in sponge-associated filamentous bacteria and theonellapeptolides in sponge-associated unicellular bacteria. A microscopic analysis of dissociated cells from Lissodendoryx sp. was also undertaken. The structures of four new halichondrins (3.13 - 3.16), isolated from Lissodendoryx sp., have been determined from spectral data. All of these compounds are very similar to known B series halichondrins, with differences occurring only beyond carbon 44. As biological activity has been shown to be derived from the portion of the molecule between carbons 1 and 35, they all retain good activity in the P388 assay as expected. A new siderophore, petrobactin sulfonate (4.2), was characterised, along with three cyclic imide siderophore derivatives (4.3 - 4.5). Petrobactin sulfonate is the first marine siderophore containing a sulfonated 3,4-dihydroxy aromatic ring. The structures were elucidated from spectral data, resulting in a revision of the NMR assignments of petrobactin.
21
Stapleton, Bronwin Louise. "Structural studies of bioactive natural products from marine invertebrates /". St. Lucia, Qld, 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16452.pdf.
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22
Pereira, Alban R. "Marine natural products : synthesis and isolation of bioactive analogues". Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/7526.
Texto completo da fonteResumo:
Tauramamide (2-12), a linear acylpentapeptide recently isolated from cultures of
Brevibacillus laterosporus (PNG-276) collected in Papua New Guinea, was synthesized in 9
steps and 29% overall yield. Besides confirming the proposed structure, synthetic (2-12)
allowed the antimicrobial assessment of this novel antibiotic. Additionally, a new analogue of
the surfactin depsipeptides family named dealkylsurfactin (2-48), was prepared in 10 steps and
14% overall yield. The compound was employed as a biological tool in binding studies between
the mitotic regulator isomerase Pinl and the microtubule-associated protein tau, a crucial
interaction involved in Alzheimer's disease.
Chemical exploration of Garveia annulata, a seasonal hydroid collected in Barkley
Sound, British Columbia, led to the isolation of twelve secondary metabolites including four new
compounds (3-53 to 3-56). Nine of these metabolites showed inhibition of indoleamine 2,3-
dioxigenase (IDO), with the annulins among the most potent in vitro IDO inhibitors isolated to
date. IDO plays a central role in immune escape, which prevents the immunological rejection of
tumors or the allogeneic fetus.
The ceratamine inspired antimitotic agent (4-142) and inactive analogue (4-157) were
synthesized in no more than 8 steps, with overall yields of 20% and 15% respectively. Activity
evaluation of these analogues suggested that potency improves with planarity and that the
synthetically laborious imidazo[4,5,d]azepine core heterocycle of ceratamines is not required for
activity.
Haplosamate A (5-62), isolated from the marine sponge Dasychalina fragilis collected in
Papua New Guinea, was found to be the first member of a new family of cannabinoid-active
sterols. Saturation transfer double-difference (STDD) NMR experiments confirmed that (5-62)specifically binds the cannabinoid human receptors CB1 and CB2 via the classical cannabinoid
pharmacophore.
A growing appreciation of the therapeutic potential of PI3K inhibitors has encouraged the
development of new inhibitory compounds with enhanced potency, selectivity and
pharmacological properties. Such substances are destined to the treatment of inflammatory and
autoimmune disorders as well as cancer and cardiovascular diseases. An optimization program
intended to develop more stable and isoform-selective PI3K inhibitors based on the marinederived
natural product liphagal (6-1), led to the preparation of a small library of synthetic
analogues.
23
Daoust, Julie. "Isolation and structure elucidation of bioactive marine natural products". Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/37536.
Texto completo da fonteResumo:
Clionamines A-D (2.6-2.9) are new aminosteroids isolated from South African specimens of the sponge Cliona celata. All four compounds (2.6-2.9) are activators of autophagy in MCF-7 cells. Autophagy is a catabolic process that plays an important role in maintaining cellular homeostasis. Autophagy is also directly involved in the removal of bacterial and viral antigens and in the development of cancerous tumors.
The novel sesterterpenoid ansellone A (3.4) was isolated from the nudibranch Cadlina luteomarginata and was later found to have been sequestered by the nudibranch from the sponge Phorbas sp. Ansellone A (3.4) is an activator of the cAMP signalling pathway. Following the isolation of 3.4, the novel sesterterpenoids ansellones B-D (4.3-4.5) as well as alotaketal E (4.6) were isolated from the sponge Phorbas sp. and were found to also be activators of the cAMP signalling pathway.
Several bacterial isolates were obtained from the sponge Phorbas sp. in order to investigate the possibility that the ansellones and the alotaketals isolated from this sponge were biosynthesized by a bacterial symbiont. Since these sesterterpenoids were activators of the cAMP signalling pathway, the investigation was conducted using bioassay guided fractionation of the bacterial isolates. The new meroterpenoid phorbasolic acid (5.1) was isolated, but no sesterterpenoids were found in the bacterial isolates.
In an effort to identify molecules with antibiotic properties, a biological assay was designed to screen for inhibitors of the citrate synthase type II enzyme. One aspect of this enzyme that is of therapeutic interest is that Gram-negative bacteria possess a very different isoform of the enzyme than Gram-positive bacteria and eukaryotes. Therefore, an antibiotic specific to type II citrate synthase would target Gram-negative bacteria selectively. An extract from a culture of Bacillus pumillus inhibited the enzyme in the assay. Although the molecule responsible for this effect has yet to be identified, the new aliphatic amide 12-methyl tridecanamide (6.1) was isolated.
24
Robinson, Paul A. "Studies towards the synthesis of marine polysulfide natural products". Thesis, Loughborough University, 2010. https://dspace.lboro.ac.uk/2134/6379.
Texto completo da fonteResumo:
Biologically active compounds isolated from marine sources have had increasing interest in recent years with significant research going into the discovery and isolation of novel marine polysulfide natural products. Varacin, probably the most widely studied marine polysulfide to date was the subject of much debated structure elucidation attempts, and more recently several successful synthetic approaches have been published. The work published aims to increase our understanding of marine polysulfide compounds existence in nature and determine the origins of their biological activity. (+)-Aplidium trisulfide which was isolated from Aplidium Sp. D in 1989 by Munro et al has been shown to exhibit in vitro antimicrobial, antileukemic and cytotoxic properties. These intriguing biological effects have led our work towards developing a novel synthetic route toward aplidium trisulfide by both chiral and racemic routes. Aplidium trisulfide is of special significance as it is very rare to isolate enantiomeric compounds from marine sources. Two other closely related marine alkaloids fasmerianamine A and B are also of synthetic interest to us due to their close resemblance to the structure of aplidium trisulfide. The fasmerianamines were isolated by Copp et al from the marine ascidian Hypsistozoa fasmeriana in 2001.
25
Roberts, Bracken. "Identification of Novel Antimalarial Scaffolds From Marine Natural Products". Master's thesis, University of Central Florida, 2012. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5464.
Texto completo da fonteResumo:
Malaria, the disease caused by Plasmodium sp., claims the lives of over 1 million people every year, with Plasmodium falciparum causing the highest morbidity. Rapidly acquiring drug resistance is threatening to exhaust our antimalarial drug arsenal and already requires the utilization of combination drug therapy in most cases. The global need for novel antimalarial chemical scaffolds has never been greater. Screening of natural product libraries is known to have higher hit rates than synthetic chemical libraries. This elevated hit rate is somewhat attributed to the greater biodiversity available in natural products. Marine life is the most biodiverse system on the planet, containing 34 of the 36 known phyla of life, and is expected to be a rich source of novel chemotypes. In collaboration with the Harbor Branch Oceanographic Institute in Ft. Pierce we have screened a library of over 2,800 marine macroorganism peak fractions against Plasmodium falciparum using the SYBR green I fluorescence-based assay. In this screening process we have identified six compounds from five novel chemical scaffolds all of which have low micromolar to submicromolar IC50 values and excellent selectivity indices. Additionally, one of these chemical scaffolds, the bis(indolyl)imidazole, was selected for further in vitro pharmacological and structure-activity relationship (SAR) profiling, key steps in the challenging process of identifying a new antimalarial drug lead compound.M.S.
Masters
Molecular Biology and Microbiology
Medicine
Biotechnology
26
Shirley, Harold John. "Synthetic investigations into alotane derived sesterterpenoid marine natural products". Thesis, Queen Mary, University of London, 2015. http://qmro.qmul.ac.uk/xmlui/handle/123456789/9110.
Texto completo da fonteResumo:
Phorbaketal A (I) and phorone A (II) are members of a growing family of biologically active sesterterpenoid natural products, derived from marine sponges. These compounds possess potent biological activities and intriguing molecular architectures, which have inspired efforts towards their total synthesis. Early work in this thesis describes how new methodology is developed aimed at the synthesis of phorbaketal A (I). The synthesis and subsequent treatment of the model hydroxyphenol III with PhI(OAc)2 led to the development of a new method for spiroketal synthesis via cascade oxidative dearomatisation. This new spiroketalisation method was then further elaborated for the total synthesis of phorbaketal A (I). This required the construction of the noralotane carbon skeleton IV, employing the union of the aryl aldehyde V and the propargylated geraniol VI. Treatment of the noralotane IV with PhI(OAc)2 gave the spiroketal VIII as a complex mixture of labile diastereomers. This new method for spiroketalisation ultimately proved unsuitable for the total synthesis of these spiroketal natural products. Following this, attempts at expanding the substrate scope for this new oxidative dearomatisation method were explored for the formation of a range of saturated spiroketals. v The second part of this thesis describes efforts towards the total synthesis of the related sesterterpenoid natural product phorone A (II). Considerable synthetic effort led to synthesis of the novel (Z)-bromoalkene IX and the drimane aldehyde X, which were coupled to give the ansellane alcohol XI, in a total of 17 steps. This work represents the first ever synthesis of the ansellane skeleton. Efforts to oxidise and cyclise the alcohol XI were initiated; however difficulties with eliminative dehydration prevented its conversion to phorone A (2). The final work in this thesis describes alternate coupling methods aimed at circumventing these unforeseen issues.
27
Hooper, Gregory John. "Biologically active natural products from South African marine invertebrates". Thesis, Rhodes University, 1997. http://hdl.handle.net/10962/d1003239.
Texto completo da fonteResumo:
This thesis describes the chemical and biological investigation of the extracts of six different marine invertebrate organisms collected along the South African coastline. The work on these extracts has resulted in the isolation and structural elucidation of twenty-one previously undescribed secondary metabolites; The history of marine natural product chemistry in South Africa has not previously been reviewed and so a comprehensive review covering the literature from the 1940's up until the end of 1995 is presented here. The marine ascidian Pseudodistoma species collected in the Tsitsikamma Marine Reserve was shown to contain four new unsaturated amino alcohols [47], [48], [49] and [50] which were isolated as their acetyl derivatives. These compounds exhibited strong antimicrobial activity. Four new pyrroloiminoquinone alkaloids, the tsitsikammamines A [90] to D [93],were isolated from a new genus of Latrunculid sponge collected in the Tsitsikamma Marine Reserve. These highly pigmented compounds also possessed strong antimicrobial activity. An investigation of two phenotypic colour variants of the soft coral Capnella thyrsoidea resulted in the isolation of the known steroid 5α-pregna-1, 20-dien-3-one [97] and an additional six new metabolites, 16β-hydroxy-5α-pregna-1 ,20-dien-3-one 16-acetate [98], 3α,16β-dihydroxy-5α-pregna-1, 20-diene 3,16-diacetate [99] and four xenicane diterpenes, the tsitsixenicins A [100] to D [103]. This is the first reported isolation of xenicane diterpenes from the soft coral family Nephtheiidae. Tsitsixenicin A and B showed good anti-inflammatory activity by inhibiting superoxide production in both rabbit and human cell neutrophils. A further four new metabolites were isolated from two soft corals which could only be identified to the genus level and were designated Alcyonium species A and species B. Alcyonium species A was collected in the Tsitsikamma Marine Reserve and yielded two new polyhydroxysterols, cholest-5-ene-3β, 7β, 19-triol 19-acetate [121] and cholest-5,24-diene-3β, 7β, 19-triol 19-acetate [122]. The soft coral Alcyonium species B was collected off Aliwal Shoal and was found to contain two known xenicane diterpenes, 9-deacetoxy-14, 15-deepoxyxeniculin [110] and zahavin A [16], and two new xenicane diterpenes, 7 -epoxyzahavin A [123] and xeniolide C [124]. Compounds [110], [16] and [123] exhibited strong anti-inflammatory activity and compounds [110] and [16] showed good antithrombotic activity. The endemic soft coral A/cyanium fauri collected at Riet Point near Port Alfred yielded the new sesquiterpene hydroquinone rietone [141] in high yierd, fogether with the minor compounds 8'-acetoxyrietone [142] and 8'-desoxyrietone [143]. Rietone exhibited moderate activity in the NCl's in-vitro anti-HIV bioassays.
28
Quan-Le, Diana Huynh. "Natural Products as Novel Therapies for Tuberculosis". Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18464.
Texto completo da fonteResumo:
Tuberculosis (TB) continues to devastate the global population as the leading cause of death from an infectious disease. TB infects over 10 million people annually and is estimated to cost the world’s economy over US$984 billion in healthcare and productivity over the next 15 years. The current TB vaccine is only partially effective in preventing infection and any protection afforded wanes over time as the recipients reach adolescence. Furthermore, current treatment programs for TB are lengthy, complex and problematic with regards to patient non-adherence and drug misuse. As TB is endemic in areas of low socioeconomic status, these issues have led to a global pandemic of multiple drug-resistant TB. There is an urgent need for a more effective vaccine and new drugs to combat the burden of TB disease. Throughout history, natural products have been the richest source of bioactive compounds as novel vaccines and therapies. In this study, samples from a library of marine organisms and extracts from sponge-associated microflora were screened for antimycobacterial activity against Mycobacterium tuberculosis, the causative agent of TB. Samples displaying inhibitory activity were then further assessed for potency, cytotoxicity, selectivity and efficacy against drug-resistant strains of M. tuberculosis. One species of marine sponge of the Tedania genus was found to yield samples with exceptionally potent antimycobacterial activity against drug-susceptible and drug-resistant strains of M. tuberculosis. These samples were found to be non-toxic against four human cell lines and yielded twelve antimycobacterial fractions upon purification via high performance liquid chromatography. Mass spectroscopy and nuclear magnetic resonance analysis of one of these fractions identified bengamide B as a potential compound for novel TB drug lead development, being highly potent, able to work in synergy with existing TB drugs, and able to inhibit intracellular and drug-resistant M. tuberculosis. Additional screening of extracts from sponge-associated microflora resulted in the identification of two chemical classes, the mycalazals and oroidins, as potent antimycobacterial compounds. They were found to be non-cytotoxic against three human cell lines and retained antimycobacterial activity at micromolar concentrations. Overall this study has identified three chemical scaffolds from the marine biosphere, the bengamides, mycalazals and oroidins, with potential for further development as novel antimycobacterial agents. Similarly, natural products such as tree bark saponin extracts and microbial components have long been used as adjuvants to boost the immunogenicity of protein subunit vaccines. The plant-derived polysaccharide, Advax™, is an immunomodulating δ-inulin formulation which was found to enhance the protective effect of the novel CysVac2 multistage fusion protein vaccine when administered in conjunction with CpG7909 oligonucleotide and murabutide. This vaccine, termed Advax4/CysVac2, was able to induce potent antigen-specific IFNγ+/TNF+/IL-2+ triple positive polyfunctional CD4+ T cell responses and significantly reduce bacterial burden in the lungs of M. tuberculosis-infected mice at both short- and long-term timepoints post-infection. The protective efficacy of Advax4/CysVac2 also correlated with the rapid influx of neutrophils, macrophages and monocytes to the site of vaccination and the expansion of CD44+ CD8+ T cells in the lungs. When dimethyldioctadecylammonium bromide (DDA) was added to Advax4/CysVac2, it significantly increased the frequency of antigen-specific IFNγ+/TNF+/IL-2+ triple positive polyfunctional CD4+ T cell responses, and resulted in lung and splenic protection at a level on par with that conferred by BCG. Both Advax4/CysVac2 and Advax4-DDA/CysVac2 are strong candidates for further preclinical evaluation as potential lead TB vaccines.
29
Ridley, Christian Perry. "Chemical and biological studies of marine natural products and marine invertebrate/bacterial symbiosis /". Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2005. http://wwwlib.umi.com/cr/ucsd/fullcit?p3167855.
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Varnavas, Christalla Zenos. "Synthetic studies directed towards sesquiterpene-phenol natural products". Thesis, University of Salford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366319.
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Gil, Escolano Alejandro. "Studies toward the synthesis of marine natural products Phormidolides B-D". Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/544128.
Texto completo da fonteResumo:
Marine natural products (MNPs) are, undoubtedly, highly valuable starting points for drug-development programs. Generally, MNPs show a well-defined spatial orientation that have evolved for thousands of years to interact with their biological target and the special and unique conditions present in seas, lakes, oceans and rivers allow the biosynthesis of highly potent compunds. Nowadays, the processes to discover a new drug from MNPs are bio-assay guided, giving more importance to the biological results rather than to the molecular structure. After a molecular entity has shown to be biologically relevant the next step is to determine the structural and stereochemical information of such molecule. It is at this step where the project described in this doctoral thesis started.
Phormidolides B, C and D (PM B-D) is a family of complex molecules that were isolated in 2010 by the pharmaceutical company Pharmamar S.A. during an expedition to collect samples in the Pemba Island (Madagascar). The extracts rendered a mixture of PM B-D that, once purified, were tested on an IC50 assay against three tumour cell lines. The results showed activity in the low micromolar range with a still unknown mechanism of action. After extensive HRMS, 1D-NMR and 2D-NMR techniques a possible structure was proposed.
Following previous UB doctoral theses (Dr. Adriana Lorente and Dr. Janire Lamariano) this doctoral thesis describes, as a compendium of publications, several synthetic studies with the final objective of achieving a robust total synthesis to confirm the structural information of PM B-D by chemical synthesis. After a general introduction (Chapter 1), Chapter 2 (Org. Lett. 2015, 17, 6246.) describes an optimization for the synthesis of the macrocyclic core present in PM B-D. Chapter 3 (Chem. Eur. J. 2016, 21, 7033.) deals, for the first time, with the synthesis and introduction of the most challenging part of the molecule: the bromo-methoxy-diene (BMD) moiety present at the end of the polyhydroxylated chain. After this finding, Chapter 4 (Org. Lett., 2016, 18, 4485.) illustrates the enantioselective synthesis of the polyol chain present in Oscillariolide and Phormidolides, including the previously mentioned BMD moiety. Chapter 5 reports the preparation of the fatty acids present in PM C and D. Finally, after the previous synthetic optimizations, Chapter 6 describes the first synthetic approach for the construction of this large family of natural products using a highly convergent approach.
Finally, as an annex a review article entitled “Role of the Nozaki-Hiayama-Kishi-Takai coupling in the synthesis of natural products” (Chem. Rev., 2017, 117, 8420.) is included to deeply explain the uses of this reaction used, as well, for the synthesis of phormidolide B-D. A section with the general conclusions extracted from this thesis is also included.Los productos naturales marítimos (MNPs) son puntos de partida muy válidos para programas de desarrollo de fármacos. Generalmente, los MNPs muestran una orientación espacial bien definida que ha evolucionado durante miles de años para interaccionar con su diana terapéutica y las condiciones especiales presentes en mares, lagos, océanos y ríos permiten la biosíntesis de compuestos de gran potencia. Las Formidolidas B, C y D (PM B-D) son una familia de policétidos que fue aislada en 2010 por la compañía farmacéutica Pharmamar S.A. durante una expedición para recoger muestras en Madagascar. Los extractos dieron una mezcla de PM B-D que, una vez purificadas, se ensayaron (IC50) contra tres líneas celulares de cáncer. Los resultados mostraron actividad en el rango micromolar con un mecanismo de acción desconocido. Utilizando técnicas de HRMS, 1D-NMR y 2D-NMR se determinó una posible estructura para esta familia de MNPs. Siguiendo el trabajo de tesis doctorales anteriores (el Dr. Adriana Lorente y el Dr. Janire Lamariano) esta tesis describe, como un compendio de publicaciones, varios estudios sintéticos para conseguir una síntesis total robusta que confirme la información estructural de las PM B-D. Después de una introducción general (Capítulo 1), en el Capítulo 2 (Org. Lett. 2015, 17, 6246.) se describe una optimización para la síntesis del núcleo macrocíclico presente en las PM B-D. En el Capítulo 3 (Chem. Eur. J. 2016, 21, 7033.) se explica, por primera vez, la síntesis e introducción de la parte más compleja de la molécula: el dominio bromo-metoxi-dieno (BMD) presente al final de cadena polihidroxilada. Después de este avance, el Capítulo 4 (Org. Lett. 2016, 18, 4485.) ilustra la síntesis enantioselectiva de la cadena poliólica presente en la Oscillariolida y en las Formidolidas. El capítulo 5 relata la preparación de los ácidos grasos presentes en las PM C y D. Finalmente, después de las optimizaciones sintéticas anteriores, el Capítulo 6 describe el primer enfoque sintético para la construcción de esta compleja familia de productos naturales usando una estrategia muy convergente. Finalmente, se incluye, como un anexo, una revisión titulada “Role of the Nozaki-Hiayama-Kishi-Takai coupling in the synthesis of natural products” (Chem. Rev, 2017, 117, 8420.) para explicar profundamente los usos de esta reacción usada, también, para la síntesis de las formidolidas B-D. Las conclusiones generales de este trabajo están comentadas al final de la presente tesis.
32
Demerdash, Amr El. "Isolation of Bioactive Marine Natural Products and Bioinspired Synthesis of Fused Guanidinic Tricyclic Analogues". Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS088.
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Le travail réalisé dans cette thèse a consisté en deux parties principales; la première partie a été centrée sur l’isolement de métabolites marins bioactifs, en mettant l'accent sur l'utilisation de techniques intégrés et modernes pour l'exploration chimique de deux éponges marines sélectionnées pour leurs activités cytotoxiques et antiinfectieuses. L’inhibition du Quorum Sensing pour explorer les activités antibiofilms a été utilisée. L’étude chimique de la première éponge Monanchora sp., a permis l'isolement et l'identification de vingt-huit composés guanidiniques et polycycliques, dont onze nouveaux. De la deuxième éponge Suberea ianthelliformi, nous avons pu isolé et identifié douze métabolites de type bropmotyrosines incluant huit alcaloïdes nouveaux dont les tétrabromotyrosines de la famille psammaplysenes. Les composés isolés ont été évalués pour leurs activités biologiques, en particulier pour les activités ciblées, cytotoxicité et inhibition de quorum sensing (QSI). De nombreux composés se sont avérés cytotoxiques sur plusieurs lignées cellulaires cancéreuses à des concentrations allant du micro au nanomolaire, en particulier les produits pentacycliques de la famille des crambescidines 800 et 814 alcaloïdes (CI50 = 4.5 nM). Ces résultats sont présentés à la fin du manuscrit. La deuxième partie concerne la synthèse bioinspirée du fragment guanidinique et tricyclique central des crambescidines et batzelladines. La synthèse totale de deux analogues tricycliques de merobatzelladine B a été ainsi réalisée. La stratégie de synthèse est essentiellement basée sur une réaction bioinspirée et inspiré de la stratégie de Robinson lors de la synthèse de la tropénoneThe work achieved in this thesis consisted two main parts; the first part was centered to the l marine natural product program, with emphasis on using modern and integrated techniecs for the chemical exploration of two promising marine sponges for the discovery of new marine secondary metaboilites along with their biological evalutions as anticancers, antibiotics, antifouling and antibiofilms. The chemical exploration of the first marine sponge Monanchora sp., afforded the isolation and identification of twenty-eight compounds, included eleven new compounds. The second marine sponge Suberea ianthelliformis, we were able to isolate and identify twelve marine metabolites included four known compounds and eight new tetrabromo tyrosine alkaloids related to psammaplysenes family. The isolated compounds were evaluated for their biological activities, in particular for cytotoxicity, quorum sensing inhibition (QSI) and antibiofilms. Almost of the isolated compounds exhibited interesting high cytotoxic activity against several cancer cell lines ranging from micro to nanomolar scale, in particular the isolated pentacyclic crambescidin 800 and 814 guanidine alkaloids showed strong cytotoxicity with IC50 = 4.5 nM. The second part was concerning with the bioinspired synthesis of the central tricyclic guanidinic fragments of the polycyclic marine alkaloids, batzelladines/crambescidins, in addition to the total synthesis of two stereoisomeric analogues of merobatzelladine B tricyclic alkaloid. Successfully, we had achieved a four steps short stratgy to access the tricyclic guanidinic portion of the batzelladine alkaloids, based on a bioinspired Robinson multicomponant reaction
33
Dzeha, Thomas Mwambire. "Cyclodepsipeptides from a Kenyan marine cyanobacterium". Thesis, Rhodes University, 2003. http://hdl.handle.net/10962/d1004961.
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An examination of an organic extract of the cyanobacterium Lyngbya majuscula collected from Wasini Island off the southern Kenyan coast led to the isolation of the known cyclodepsipeptide antanapeptin A (7), recently isolated from a Madagascan collection of L. majuscula, and a new bioactive cyclodepsipeptide, homodolastatin 16 (42). Although L. majuscula is a common, pantropical cyanobacterium this study represents the first investigation of the natural product chemistry of a Kenyan population of L. majuscula. The structures of the two cyclodepsipeptides were determined from 2D NMR and mass spectrometry data. The L- stereochemistry of the proline, valine, and N-methylphenylalanine amino acids in 7 and the L – proline configuration in 42, was confirmed by Marfey’s HPLC method. Chiral GC was used to determine the absolute stereochemistry of the hydroxyisovaleric acid moiety in 7 and 42, the lactate residue in 42 and tentatively propose an L-stereochemistry for the Nmethylisoleucine amino acid in 42. Homodolastatin 16, a higher homologue of the potential anti-cancer agent, dolastatin 16, exhibited moderate activity against two oesophageal cancer cell lines.
34
Yan, Luping. "Bioactive marine natural products : analogue synthesis, SAR, and target identification". Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/50069.
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3,6,7-trihydroxycoumarin C11 (2.14) was first isolated from the green alga Dasycladus vermicularis in 1983. C11 and 3,7,8-trihydroxycoumarin C21 (2.15), alongside their precursors C12 (2.18) and C22 (2.20), were synthesized for a target-based screen for anti-HCV drugs, where ideal hits eliminate fluorescence signals by inhibiting the proteolytic activity of HCV NS3pro/Pep4A against a synthetic peptide “BS-IQFS”. With C12 and C22 serving as negative controls, C11 and C21 inhibited the NS3pro/Pep4A activity in vitro. The IC₅₀’s of C11 and C21 were 3.07 μM and 2.10 μM, respectively.
A bioassay-guided fractionation identified sintokamides A – E (3.11 – 3.15) from extracts of the sponge Dysidea sp. in 2008. In a phenotypic screen, the chlorinated dipeptides showed strong to modest inhibition of luciferase activity caused by AR NTD transactivation in LNCaP cells. Larger quantities of sintokamides A and B were isolated from the sponge for further biological study. After developing a practical synthetic route, a comprehensive SAR of the sintokamides was available from the in vitro activities of 29 synthetic analogues/precursors based on a 1,17-dinorsintokamide skeleton. LPY26 [(4R,10R)-3.233] showed the best biological activity in the synthetic analogues prepared to date and it was selected as a drug lead. Mechanism of action study using synthetic probes LPY30 (4.7) and LPY31 (4.8) revealed that the hexachlorinated 1,17-dinorsintokamides covalently bound to the AR, but not to the same AF1 region in the AR NTD as EPI-001 (3.8).
The structure of latonduine A (5.1) isolated from the sponge Stylissa carteri and its total synthesis were published in 2003. Later, latonduine A was shown to be active in a phenotypic screen to find drug leads for the treatment of cystic fibrosis caused by the F508del mutation. Latonduine A could efficiently correct immunofluorescent F508del-CFTR trafficking from the endoplasmic reticulum to the plasma membrane in the engineered cells. Synthetic latonduine A and N-biotinylated latonduine A (5.17) were prepared to support biological studies aimed at identifying its cellular protein target(s). These studies culminated in the finding that latonduine A is an inhibitor of PARP-3 with an EC₅₀ of 400 pM in CFBE41o- cells.Science, Faculty of
Chemistry, Department of
Graduate
35
Hellou, Jocelyne. "Studies in Marine Natural Products : Onchidoris bilamellata, Nanaimoal and Capnellene". Thesis, University of British Columbia, 1985. http://hdl.handle.net/2429/25822.
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The following thesis is divided into three chapters. The first describes the isolation and identification of a sphingolipid L from the methanolic skin extract of the British Columbia nudibranch Onchidoris bilamellata. The long chain base has been identified as (E)-l,3-dihydroxy-2-amino-16-methyl-4-octadecene (1̲3) and the fatty acid moiety as palmitic acid (1̲2). This ceramide possesses antibacterial activity towards the microorganisms Bacillus subtilis and Staphylococcus aureus.
[formula omitted]
The second chapter presents our attempt to synthesize a hypothetical structure of nanaimoal (2̲4), a marine sesquiterpenoid, isolated from the British Columbia nudibranch Acanthadoris nanaimoensis. The proposed route envisaged photolysis of a 2,2,10,10-tetrasubstituted cyclodecanone. This work lend to a study of the solution photochemistry of 2,2,10-trimethyl-cyclodecanone (3̲5).
[formula omitted]
The last chapter outlines studies directed toward the synthesis of capnellene (5̲1), a tricyclopentanoid obtained by Djerassi and co-workers from the soft coral Capnel laimbricata. Starting with an improved synthesis of the known ketone
Δ¹̕̕̕⁵-bicyclo[3.3.0] octen-2-one (1̲3̲8), an acylation method was developed for the preparation of Δ¹̕⁵-3-carboethoxybicyclo-[3.3.0] octen-2-one (1̲6̲0). The procedure is of general utility and has been extended to related ketones. This unsaturated keto-ester underwent a Michael addition with methyl vinyl ketone to give 1̲7̲8. Selective Knoevenagal condensation of the methyl ketone produced Δ¹̕⁵-3-carboethoxy-3-(dimethyl-3-methyl-3-butenyl-4,4-dicarboxylate)-bicyclo[3.3.0] octen-2-one (179). Reduction of the unsaturated ketone and dehydration of the allylic alcohol produced a 1,1,3,4-tetrasubstituted cyclopentadiene derivative 1̲8̲1. Intramolecular Diels-Alder cyclization of the latter afforded the tetracyclic tricarboxylic ester 1̲8̲2. Selective hydrolysis of the malonic estertricarboxylic ester 1̲8̲2 followed by decarboxylation led to 1̲8̲3, a key intermediate for the ultimate construction of the capnellane ring system.
[formula omitted]Science, Faculty of
Chemistry, Department of
Graduate
36
Kasprzyk, Milena, e milena kasprzyk@freehills com. "Synthetic Studies Towards the Tridachione Family of Marine Natural Products". Flinders University. Chemistry, Physics and Earth Sciences, 2008. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20081107.085933.
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Since the middle of the 20th century, significant interest has evolved from the scientific community towards the polypropionate family of marine natural products. A number of these compounds have been shown to possess significant biological activity, and this property, as well as their structural complexity, has driven numerous efforts towards their synthesis. The first chapter provides an introduction into the world of polypropionates, with a discussion on synthetic studies into a number of members of the tridachiapyrone family. Fundamental synthetic concepts utilised in this thesis towards the preparation of polyketides are also described, with a focus on their application towards the synthesis of 9,10-deoxytridachione, anti tridachiahydropyrone and syn tridachiahydropyrone.
Chapter 2 describes the work undertaken towards the total synthesis of 9,10-deoxytridachione. The novel tandem conjugate addition-Dieckmann condensation of complex enones developed previously in the Perkins group was used to generate anti methylated cyclohexenones as key synthetic intermediates. The conversion of the cyclohexenones into the corresponding cyclohexadienes via allylic alcohols was attempted, utilising a Grignard-mediated reaction to achieve the selective 1,2-reduction. Studies into the Grignard-mediated reduction were also undertaken on seven additional cyclohexenones, in order to investigate the utility and scope of the reaction.
The extension of the methodology previously developed for the synthesis of cyclohexenones is the subject of Chapter 3. This section describes investigations into the synthesis of stereochemically-diverse cyclohexenones from complex enones. The conjugate addition-Dieckmann condensation strategy was extended successfully towards the synthesis of a syn methylated cyclohexenone, which allowed the synthesis of the proposed true structure of tridachiahydropyrone to be pursued.
The methodology developed in Chapter 3 was utilised in Chapter 4 to synthesise a model system of syn tridachiahydropyrone. A comparative analysis of the NMR data of the syn model, an anti model and anti tridachiahydropyrone with the natural product indicated that the true structure of tridachiahydropyrone may indeed have syn stereochemistry. The synthesis of syn tridachiahydropyrone was attempted, and to this end a suitable cyclohexanone was successfully synthesised. However, the subsequent methylation-elimination cascade failed to furnish the desired syn methylated cyclohexenone, producing only an anti methylated cyclohexanone. The stereochemistry of the methylation was deduced using high and low variable temperature NMR coupled with selective irradiation NOESY.
37
Sigerson, Ralph Clark. "Formal synthesis of the asbestinin family of marine natural products". Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3835/.
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The asbestinins are a sub-class of the ether bridged 2,11-cyclised cembranoid family of marine natural products that have been isolated from octocoral species Briareum Asbestinum. They exhibit high structural complexity and a diverse range of bioactivities that include cytotoxicity against tumour cell lines, potent anti-bacterial properties and antagonism of both histamine and acetylcholine. This report presents the continued efforts in developing an efficient synthetic route to the asbestinins which will be general enough to enable the synthesis of virtually every member of this family of compounds. The key synthetic steps include; a samarium diiodide reductive cyclisation to generate 2,6-syn-5,6-anti tetrahydropyranol motif, oxonium ylide formation with subsequent [2,3]-sigmatropic rearrangement of a functionalised diazoketone and an intramolecular Diels-Alder cycloaddition to construct the cyclohexyl ring. Many studies have been carried out on other sub-classes within the ether bridged 2,11-cyclised cembranoid family of natural products, of particular interest have been the sarcodictyins and cladiellins, the latter of which has been extensively investigated within the Clark group.
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Beukes, Denzil Ronwynne. "Structural and synthetic investigations of South African marine natural products". Thesis, Rhodes University, 2000. http://hdl.handle.net/10962/d1005015.
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A chemical investigation of six different marine invertebrates, collected along the South African coastline, resulted in the isolation and structural elucidation of fifteen previously undescribed secondary metabolites along with seven known compounds. The structures of the new metabolites were determined by a combination of spectroscopic and chemical methods. The endemic false limpet Siphonaria capensis was shown to contain two unusual polypropionate metabolites capensinone (162) and capensifuranone (163) as well as 2,4,6,8-tetramethyl-2-undecenoic acid (164) and the known polypropionates (E)- and (Z)siphonarienfuranone (149 and 161). Capensinone is the first example of a marine polypropionate containing a cyc1opentenone moiety. An investigation of the endemic South African soft coral Pieterfaurea unilobata yielded six new, highly oxygenated, pregnadiene sterols (180-185) and the known metabolite (169). Compounds 180-185 are the first pregnadienes obtained from the marine environment containing a C-7 substituent. An alternative procedure for the quick assignment of the absolute configuration at C-3 in this series of compounds was proposed. A companson of the pyrroloiminoquinone alkaloids of three undescribed l'}trunculid sponges resulted in the isolation of 3-dih¥drodiscorhabdin C (243), 3-dihydrodiscorhabdin B (244), discorhabdin H (197) and the previously reported alkaloids discorhabdin A (189) and discorhabdin D (192). While all three sponges were found to be morphologically different they all contained discorhabdin A as the major metabolite and discorhabdin H as one of their minor metabolites. It was found that a feature common to most of the South African latrunculid sponges is the reduction of the C-3 carbonyl gr,o up in some of the minor metabolites. The indole alkaloids, dilemmaones A-C (261-263), containing an unusual cyc1opentanone-indole skeleton, were isolated in trace amounts by bioassay guided fractionation of an extract obtained from a mixed collection of sponges collected near Cape Town. In an attempt to acquire more of these novel compounds for further investigation of their biological activity, several synthetic strategies towards their total synthesis were explored. A key feature of these approaches was the exploitation of the regioselective Gassman's artha-alkylation procedure for the introduction of an aromatic methyl substituent.
39
Henderson, James A. "Synthesis of marine natural products: Aburatubolactam A and the halichondrins". Connect to online resource, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3308674.
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Blackburn, Christine Lynn. "The effects of marine natural products on basic cellular processes /". Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2001. http://wwwlib.umi.com/cr/ucsd/fullcit?p3035897.
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Lerata, Mookho Sylvia. "Discovery of cytotoxic natural products from South African marine sponges". University of the Western Cape, 2018. http://hdl.handle.net/11394/6447.
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Magister Pharmaceuticae - MpharmCancer is a major health problem worldwide and killing millions of people each year. The use of natural products as chemotherapeutic agents is well established, however, many of the currently available drugs are associated with undesirable side effects and high toxicity. Furthermore, the development of drug resistant cancers makes the search for anticancer lead compounds a priority. In this study a library of prefractionated marine sponge extracts was established and used to prioritise samples for isolation of bioactive metabolites. From the generated library, two of the sponges of genera Ircinia sp. and Latrunculid sp. resulted in isolation of furanosesterterpenes (7E,12Z,20Z,18S-variabilin) and pyrroloiminoquinone (tsitsikammamine A and tsitsikammamine N-18 oxime) alkaloids respectively. The structures of these compounds were elucidated by analysis of 1D and 2D NMR data. These compounds displayed moderate to potent cytotoxicity against MCF-7, PC-3, U-87 and HEK-293 cells lines through apoptosis, with lack of selectivity for cancer cell lines.
42
Krzysiak, Amanda J. "The isolation and characterization of natural products from marine plants and microorganisms /". Electronic version (PDF), 2006. http://dl.uncw.edu/etd/2006/krzysiaka/amandakrzysiak.pdf.
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Dyson, Bryony Sara. "Determining the structures of halogenated marine natural products by total synthesis". Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:31737a99-a13c-4110-b36d-1c043b66565b.
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Elatenyne, a brominated C15 acetogenin isolated from the red Laurencia elata marine algae, was originally assigned a pyranopyran structure. Previous total synthesis of the pyranopyran structure has found this assignment to be incorrect. During this work the revised 2,2’-bifuranyl skeleton of elatenyne was suggested, but this skeleton has 32 possible diastereomers. The most likely diastereomer of elatenyne was predicted using computational 13C NMR chemical shift calculation in combination with the possible stereochemical outcomes from the proposed biosynthesis. Chapter 1 introduces the structural misassignment of natural products and describes the misassignment of elatenyne as well as a related chloro enyne. The use of computational methods and biosynthetic postulates to aid structure elucidation are also discussed. Chapter 2 describes the first generation synthesis of cross metathesis coupling partners required for the synthesis of elatenyne from D-mannitol. Chapter 3 describes the completed total synthesis of elatenyne, along with three derivatives and the (E)-isomer of elatenyne; itself a natural product. A comparison of the synthetic data with the isolation data for the natural products is presented, as well as comparison with the synthetic material of Kim and co-workers whose concurrent biomimetic total synthesis is also presented. Chapter 4 describes the modular nature of the devised synthetic route to access any diastereomer of elatenyne and its application to related 2,2’-bifuranyl natural products.
44
Lane, Amy L. "Marine natural products as antimicrobial chemical defenses and sources of potential drugs". Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/26556.
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Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2009.Committee Chair: Kubanek, Julia; Committee Member: Fernandez, Facundo M.; Committee Member: Harvey, Stephen C.; Committee Member: Hay, Mark E.; Committee Member: Hud, Nicholas V. Part of the SMARTech Electronic Thesis and Dissertation Collection.
45
Winter, Jaclyn Marie. "Investigating the biosynthesis of halogenated meroterpenoid natural products from marine actinomycetes". Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/ucsd/fullcit?p3397239.
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Thesis (Ph. D.)--University of California, San Diego, 2010.Title from first page of PDF file (viewed March 31, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
46
Li, Hang, e n/a. "Chemical investigations of Natural Products from Australian Marine Sponge-Derived Fungi". Griffith University. Eskitis Institute for Cell and Molecular Therapies, 2007. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20081103.091038.
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This thesis described the chemical investigations of natural products from Australian marine sponge-derived fungi. Sponge samples were collected from the Great Barrier Reef, Queensland, Australia, by Queensland Museum. The thesis is divided into eight chapters and can be devided into two major parts. The first three chapters comprised the first part of the thesis: Chapter 1 outlined the research background, literature review of marine fungal secondary metabolites; Chapter 2 introduced fungal culture and storage background knowledge, and the list of isolated marine fungal strains. Chapter 3 introduced the background of the thrombin inhibition assay and assay results.
The second part (Chapter 4 to 7) of this thesis is focused on chemical isolation and structure elucidation of secondary metabolites from isolated fungal strains, mostly active strains against thrombin. An unidentified fungal strain, FS-G315858 (T)-Y, isolated from the frozen sponge sample Dysidea sp.1400 produced five peptide compounds (chapter 4, 16-20). Compound 16 is a polypeptide which features the same relative configuration with a known compound unguisine A, and compounds 17-20 are diketopiperazines.
Active fungal strains FS-G315695 (T)-Y and FDPS-61732-YB were isolated from different sponge samples. However, they were identified to be the identical fungal strain Eurotium rubrum; the chemical isolation of FS-G315695 (T)-Y from its mycelia EtOAc extract resulted in three compounds (chapter 5, 17-19). Compounds 18 and 19 were identified to be flavoglaucin and iso-dihydroauroglaucin. Compound 17 was identified to have the same relative configuration with a known compound neo-echinulin A. The chemical isolation of FDPS-61732-YB from its broth EtOAc extract resulted in several diketopiperazines (chapter 5, 27-29).
Another active fungal strain FS-G315695 (T)-WY was identified as Aspergillus ochraceous, the chemical isolation of its mycelia EtOAc extract resulted in one benzodiazepine compound (chapter 6, 18), together with two fatty acids (chapter 6, 16-17). The structure of compound 18 was elucidated and identified to have same relative configuration with the known compound circumdatin E.
Media comparison for active fungal strain FS-G315695 (T)-Y was conducted and this work resulted in producing several neo-echinulin analogues (chapter 7, 1-3). The isolation and structure elucidation of these compounds were reported in chapter 7.
47
Boot, Claudia M. "Marine-derived fungi : an effective source of novel bioactive natural products /". Diss., Digital Dissertations Database. Restricted to UC campuses, 2007. http://uclibs.org/PID/11984.
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Alvarado, Stephenie M. "Identification of novel antimalarials from marine natural products for lead discovery". Master's thesis, University of Central Florida, 2010. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/4591.
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An estimated 500 million cases of malaria occur each year. The increasing prevalence of drug resistant strains of Plasmodium in most malaria endemic areas has significantly reduced the efficacy of current antimalarial drugs for prophylaxis and treatment of this disease. Therefore, discovery of new, inexpensive, and effective drugs are urgently needed to combat this disease. Marine biodiversity is an enormous source of novel chemical entities and has been barely investigated for antimalarial drug discovery. In an effort to discover novel therapeutics for malaria, we studied the antimalarial activities of a unique marine-derived peak fraction library provided by Harbor Branch Oceanographic Institute (HBOI). Within this unique library, we have screened 2,830 marine natural product (MNP) peak fractions through a medium throughput screening effort utilizing the SYBR Green-I fluorescence based assay, and have identified 253 fractions that exhibit antimalarial activity. From those inhibiting fractions we have identified twenty species of marine organisms that inhibit Plasmodium falciparum growth, from which thirty-five fractions were selected for further study. Among those thirty-five, eighty-three percent were also found to inhibit the chloroquine resistant strain of P. falciparum, Dd2. The most potent inhibitors were then screened for their cytotoxic properties using the MTT cell viability assay. Among the samples that exhibited potent inhibition of P. falciparum growth were fractions derived from a sponge of the genus Spongosorites sp.. This genus of sponge has been reported to contain the nortopsentin and topsentin class of bis-indole imidazole alkaloids. Nortopsentin A inhibited the parasite growth at the trophozoite stage with an IC[sub]50 value of 1.6micrometer]. This is the first report of antimalarial activity for this class of compound.ID: 030423269; System requirements: World Wide Web browser and PDF reader.; Mode of access: World Wide Web.; Thesis (M.S.)--University of Central Florida, 2010.; Includes bibliographical references (p. 56-61).
M.S.
Masters
Burnett School of Biomedical Sciences
Medicine
49
Rapson, Trevor Douglas. "Bioactive 4-methoxypyrrolic natural products from two South African marine invertebrates". Thesis, Rhodes University, 2005. http://hdl.handle.net/10962/d1006766.
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This thesis presents an investigation of the 4-methoxypyrrolic constituents of two South African marine invertebrates, the nudibranch Tambja capensis and the bryozoan Bugula dentata. Three known compounds tambjamine A (7), tambjamine E (13) and the tetrapyrrole (15) were isolated during this investigation. All three compounds were shown to be active against oesophageal cancer in accordance with the general anticancer and immunosuppressive properties observed for 4-methoxypyrrolic natural products. Tambjamine A (7), tambjamine E (13) and the tetrapyrrole (15), together with tambjamine K (21) and L (22) (previously isolated in our laboratory) were used as standards to quantitatively assess the presence of these tambjamines in T. capensis and B. dentata collected from three different sites along the South African coast. This study confirmed that B. dentata is the source of the 4-methoxypyrrolic natural products sequestered by T. capensis and eliminated the closely related bryozoan B. neritina as a source of these metabolites. The paucity of tambjamine L (21) and K (22) obtained in previous investigations of the sequestered chemistry of T. capensis prompted an attempt at the development of synthetic methodology that could be used to synthesize tambjamines in sufficient yield for in depth bioactivity studies. In order to by pass the extensively reported problems associated with the synthesis of this group of compound 3-methoxy-2-formylpyrrole (47), readily accessible from 3-methoxypyridine N-oxide (48), was used as the starting material in a singlet oxygen induced 2,2’ bipyrrole coupling reaction. Although 47 proved unreactive in this coupling reaction, when the N-Boc protected analogue of 47 was used, and the reaction worked up in the dark, the novel methyl 4-aza-5-oxo-6,6-di-(2-pyrrolyl)-2(Z)-hexenoate (57) was obtained in low yield. The physical properties of tambjamine (E) (13) and the tetrapyrrole (15) were investigated to further the understanding of the proposed oxidative DNA cleavage mechanism and to determine the potential of the 4-methoxypyrrolic natural products as photodynamic therapy agents.
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Young, Ryan Mark. "Synthetic and bioactivity studies of antiplasmodial and antibacterial marine natural products". Thesis, Rhodes University, 2012. http://hdl.handle.net/10962/d1005043.
Texto completo da fonteResumo:
This thesis is divided into two parts, assessing marine and synthetic compounds active firstly against Plasmodium falciparum (Chapter 3 and 4) and secondly active against methicillin resistant Staphylococcus aureus (MRSA, Chapter 5). In Chapter 3 the synthesis of nine new tricyclic podocarpanes (3.203-3.207 and 3.209-3.212) from the diterpene (+)-manool is described. Initial SAR study of synthetic podocarpanes concluded that the most active compound was a C-13 phenyl substituted podocarpane (3.204, IC₅₀ 6.6 μM). By preparing analogues with varying halogenated substituents on the phenyl ring (3.209-3.212) the antiplasmodial activity was improved (IC₅₀ 1.4 μM), while simultaneously decreasing the haemolysis previously reported for this class of compounds. Inspired by the antiplasmodial activity of Wright and Wattanapiromsakul’s tricycle marine isonitriles (2.16-2.21 and 2.24-2.27) an unsuccessfully attempt was made to convert tertiary alcohol moieties to isonitrile functionalities in compounds 3.188, 3.204-3.207 and 3.209-3.212. Over a decade ago Wright et al. proposed a putative antiplasmodial mechanism of action for marine isonitriles (2.4, 2.9, 2.15, 2.19 and 2.35) and isothiocyanate (2.34) which involved interference in haem detoxification by P. falciparum thus inhibiting the growth of the parasite. In Chapter 4 we describe how we successfully managed to scale down Egan’s β-haematin inhibition assay for the analyses of small quantities of marine natural products as potential β-haematin inhibitors. Our modified assay revealed that the most active antiplasmodial marine isonitrile 2.9 (IC₅₀ 13 nM) showed total β-haematin inhibition while 2.15 (IC₅₀ 81 nM) and 2.19 (IC₅₀ 31 nM) showed partial inhibition at three equivalents relative to haem. Using contempary molecular modelling techniques the charge on the isonitrile functionality was more accurately describe and the modified charge data sets was used to explore docking of marine isonitriles to haem using AutoDock. In Chapter 5 we describe how a lead South African marine bisindole MRSA pyruvate kinase inhibitor (5.8) was discovered in collaboration with colleagues at the University of British Columbia (UBC) and how this discovery inspired us to design a synthetic route to the dibrominated bisindole, isobromotopsentin (5.20) in an attempt to increase the bioactivity displayed by 5.8. We devised a fast and high yielding synthetic route using microwave assited organic synthesis. We first tested this synthesis using simple aryl glyoxals (5.27-5.32) as precursors to synthesize biphenylimidazoles (5.21-5.26), which later allowed us to synthesize the ascidian natural product 5.111. This method was sucessfully extended to the synthesis of deoxytopsentin (5.33) from an N-Boc protected indole methyl ketone (5.89). We subsequently were able to effectively remove the carbamate protection via thermal decomposition by heating the protected bisindole imidazole (5.90) in a microwave reactor for 5 min under argon. The synthesis of 5.20 resulted in an inseparable mixture of monoprotected and totally deprotected topsentin products, and due to time constraints we were not able to optimise this synthesis. Nonetheless our synthesis of the marine natural product 5.33 which was faster and higher yielding than previously reported routes could be extended to the synthesis of other topsentin bisindoles (5.138-5.140). Work towards this goal continues in our laboratory.